Abstract Recombinant monoclonal antibodies considered a new modality of therapeutic treatment to fight viral infections. A particular challenge for viral mAb development is the isolation and characterization of mAbs with broadly neutralizing activity (bNAbs) against multiple members of a single viral family to provide an immunotherapeutic advantage, particularly for infectious agents whose cases can progress rapidly toward serious disease. Our goal for the identification of bNAbs is protein engineering by a synergistic combination of computational and experimental methods, to enhance the breadth and potency of a specific mAb using designed mutations. Phage display provides an efficient way to randomly explore up to 1010 unique library members simultaneously. However, a typical antibody-antigen interface of ~15 residues present a combinatorial possibility of 2015 mutational variants, only a fraction of which can be sampled. As a result, phage display and other antibody combinatorial methods are reliant on restriction of either amino acid diversity or interfacial positions, which limits the effectiveness of the approach. To circumvent this limitation, we propose to develop an interdisciplinary approach where computationally designed, residue-based pharmacophore descriptions of the antibody-antigen interface are used to direct the library design in subsequent phage display experiments. As a test bed for this method, we will engineer novel bNAbs against flaviviruses, which include the globally important pathogens dengue virus and Zika virus.